This invention is directed to pharmaceutical compositions containing aminothiazole compounds for inhibiting cyclin-dependent kinases (CDKs), such as CDK1, CDK2, CDK4, and CDK6. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds and to methods of treating malignancies and other disorders by administering effective amounts of such compounds.
Uncontrolled cell proliferation is the insignia of cancer. Cell proliferation in response to various stimuli is manifested by a deregulation of the cell division cycle, the process by which cells multiply and divide. Tumor cells typically have damage to the genes that directly or indirectly regulate progression through the cell division cycle.
CDKs constitute a class of enzymes that play critical roles in regulating the transitions between different phases of the cell cycle, such as the progression from a quiescent stage in G1 (the gap between mitosis and the onset of DNA replication for a new round of cell division) to S (the period of active DNA synthesis), or the progression from G2 to M phase, in which active mitosis and cell-division occur. See, e.g., the articles compiled in Science, vol. 274 (1996), pp. 1643-1677; and Ann. Rev. Cell Dev. Biol., vol. 13 (1997), pp. 261-291. CDK complexes are formed through association of a regulatory cyclin subunit (e.g., cyclin A, B1, B2, D1, D2, D3, and E) and a catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). As the name implies, the CDKs display an absolute dependence on the cyclin subunit in order to phosphorylate their target substrates, and different kinase/cyclin pairs function to regulate progression through specific portions of the cell cycle.
The D cyclins are sensitive to extracellular growth signals and become activated in response to mitogens during the G1 phase of the cell cycle. CDK4/cyclin D plays an important role in cell cycle progression by phosphorylating, and thereby inactivating, the retinoblastoma protein (Rb). Hypophosphorylated Rb binds to a family of transcriptional regulators, but upon hyperphosphorylation of Rb by CDK4/cyclin D, these transcription factors are released to activate genes whose products are responsible for S phase progression. Rb phosphorylation and inactivation by CDK4/cyclin D permit passage of the cell beyond the restriction point of the G1 phase, whereupon sensitivity to extracellular growth or inhibitory signals is lost and the cell is committed to cell division. During late G1, Rb is also phosphorylated and inactivated by CDK2/cyclin E, and recent evidence indicates that CDK2/cyclin E can also regulate progression into S phase through a parallel pathway that is independent of Rb phosphorylation (see Lukas et al., xe2x80x9cCyclin E-induced S Phase Without Activation of the pRb/E2F Pathway,xe2x80x9d Genes and Dev., vol. 11 (1997), pp. 1479-1492).
The progression from G1 to S phase, accomplished by the action of CDK4/cyclin D and CDK2/cyclin E, is subject to a variety of growth regulatory mechanisms, both negative and positive. Growth stimuli, such as mitogens, cause increased synthesis of cyclin D1 and thus increased functional CDK4. By contrast, cell growth can be xe2x80x9creined in,xe2x80x9d in response to DNA damage or negative growth stimuli, by the induction of endogenous inhibitory proteins. These naturally occurring protein inhibitors include p21WAF1/CIP1, p27KIP1, and the p16INK4 family, the latter of which inhibit CDK4 exclusively (see Harper, xe2x80x9cCyclin Dependent Kinase Inhibitors,xe2x80x9d Cancer Surv., vol. 29 (1997), pp. 91-107). Aberrations in this control system, particularly those that affect the function of CDK4 and CDK2, are implicated in the advancement of cells to the highly proliferative state characteristic of malignancies, such as familial melanomas, esophageal carcinomas, and pancreatic cancers (see, e.g., Hall and Peters, xe2x80x9cGenetic Alterations of Cyclins, Cyclin-Dependent Kinases, and CDK Inhibitors in Human Cancer,xe2x80x9d Adv. Cancer Res., vol. 68 (1996), pp. 67-108; and Kamb et al., xe2x80x9cA Cell Cycle Regulator Potentially Involved in Genesis of Many Tumor Types,xe2x80x9d Science, vol. 264 (1994), pp. 436-440). Over-expression of cyclin D1 is linked to esophageal, breast, and squamous cell carcinomas (see, e.g., DelSal et al., xe2x80x9cCell Cycle and Cancer: Critical Events at the G1 Restriction Point,xe2x80x9d Critical Rev. Oncogenesis, vol. 71 (1996), pp. 127-142). Genes encoding the CDK4-specific inhibitors of the p16 family frequently have deletions and mutations in familial melanoma, gliomas, leukemias, sarcomas, and pancreatic, non-small cell lung, and head and neck carcinomas (see Nobori et al., xe2x80x9cDeletions of the Cyclin-Dependent Kinase-4 Inhibitor Gene in Multiple Human Cancers,xe2x80x9d Nature, vol. 368 (1994), pp. 753-756). Amplification and/or overexpression of cyclin E has also been observed in a wide variety of solid tumors, and elevated cyclin E levels have been correlated with poor prognosis. In addition, the cellular levels of the CDK inhibitor p27, which acts as both a substrate and inhibitor of CDK2/cyclin E, are abnormally low in breast, colon, and prostate cancers, and the expression levels of p27 are inversely correlated with the stage of disease (see Loda et al., xe2x80x9cIncreased Proteasome-dependent Degradation of the Cyclin-Dependent Kinase Inhibitor p27 in Aggressive Colorectal Carcinomas,xe2x80x9d Nature Medicine, vol. 3 (1997), pp. 231-234). The p21 proteins also appear to transmit the p53 tumor-suppression signal to the CDKs; thus, the mutation of p53 in approximately 50% of all human cancers may indirectly result in deregulation of CDK activity.
The emerging data provide strong validation for the use of compounds inhibiting CDKs, and CDK4 and CDK2 in particular, as anti-proliferative therapeutic agents. Certain biomolecules have been proposed for this purpose. For example, U.S. Pat. No. 5,621,082 to Xiong et al. discloses nucleic acid encoding an inhibitor of CDK6, and European Patent Publication No. 0 666 270 A2 describes peptides and peptide mimetics that act as inhibitors of CDK1 and CDK2. Several small molecules have been identified as CDK inhibitors (for a recent review, see Webster, xe2x80x9cThe Therapeutic Potential of Targeting the Cell Cycle,xe2x80x9d Exp. Opin. Invest, Drugs, vol. 7 (1998), pp. 865-887). The flavone flavopiridol displays modest selectivity for inhibition of CDKs over other kinases, but inhibits CDK4, CDK2, and CDK1 equipotently, with IC50s in the 0.1-0.3 xcexcM range. Flavopiridol is currently in Phase II clinical trials as an oncology chemotherapeutic (Sedlacek et al., xe2x80x9cFlavopiridol (L86-8275; NSC 649890), A New Kinase Inhibitor for Tumor Therapy,xe2x80x9d Int. J. Oncol., vol. 9 (1996), pp. 1143-1168). Analogs of flavopiridol are the subject of other publications, for example, U.S. Pat. No. 5,733,920 to Mansuri et al. (International Publication No. WO 97/16447) and International Publication Nos. WO 97/42949, and WO 98/17662. Results with purine-based derivatives are described in Schow et al., Bioorg. Med. Chem. Lett., vol. 7 (1997), pp. 2697-2702; Grant et al., Proc. Amer. Assoc. Cancer Res,. vol. 39 (1998), Abst. 1207; Legravend et al., Bioorg. Med. Chem. Lett., vol. 8 (1998), pp. 793-798; Gray et al., Science, vol. 281 (1998), pp. 533-538; and Furet et al., 216th ACS Natl. Mtg. (Aug. 23-27, 1998, Boston), Abst MEDI-218. In addition, the following publications disclose certain pyrimidines that inhibit cyclin-dependent kinases and growth-factor mediated kinases: International Publication No. WO 98/33798; Ruetz et al., Proc. Amer. Assoc. Cancer Res,. vol. 39 (1998), Abst. 3796; and Meyer et al., Proc. Amer. Assoc. Cancer Res., vol. 39 (1998), Abst. 3794.
There is still a need, however, for small-molecule compounds that may be readily synthesized and are potent inhibitors of one or more CDKs or CDK/cyclin complexes. Because CDK4 may serve as a general activator of cell division in most cells, and because complexes of CDK4/cyclin D and CDK2/cyclin E govern the early G1 phase of the cell cycle, there is a need for effective and specific inhibitors of CDK4 and/or CDK2 for treating one or more types of tumors.
Accordingly, one object of the invention is to attain compounds and drug compositions that inhibit the activity of one or more CDKs, such as CDK2, CDK4, and/or CDK6, or cyclin complexes thereof. A further object is to provide an effective method of treating cancer indications through CDK inhibition, preferably through inhibition of CDK4 or CDK4/D-type cyclin complexes and/or CDK2 or CDK2/E-type cyclin complexes. Another object is to achieve pharmaceutical compositions containing compounds effective to block the transition of cancer cells into their proliferative phase. These and other objects and advantages of the invention, which will become apparent in light of the detailed description below, are achieved through cell-cycle control agents of the invention described below.
In one general aspect, the invention relates to pharmaceutical compositions comprising:
(a) a cell-cycle control agent selected from:
(i) compounds of the Formula I: 
xe2x80x83wherein:
R1 is a substituted or unsubstituted group selected from: C1-6-alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl); C1-6-alkenyl; C1-6-alkynyl; C1-6-alkoxyl; C1-6-alcohol; carbocyclic or heterocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) or heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, morpholinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); carbonyl (e.g., carboxyl, ester, aldehyde, or ketone); ether; (C1-6-alkyl)-carbonyl; (C1-6-alkyl)-aryl; (C1-6-alkyl)-cycloalkyl; (C1-6-alkyl)-(C1-6-alkoxyl); aryl-(C1-6-alkoxyl); thioether (e.g., aryl-S-aryl, cycloalkyl-S-aryl, cycloalkyl-S-cycloalkyl, or dialkyl sulfide); thiol; and sulfonyl; and
R2 is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure;
where each optional substituent for R1 and R2 is independently a halogen (e.g., chloro, iodo, bromo, or fluoro); oxygen (xe2x95x90O); haloalkyl (e.g., trifluoromethyl); C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; hydroxyl; C1-6-alkoxyl; carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester;
(ii) pharmaceutically acceptable salts of compounds of the Formula I; and
(iii) prodrugs and pharmaceutically active metabolites of compounds of the Formula I or pharmaceutically acceptable salts thereof; and
(b) a pharmaceutically acceptable carrier.
In a further general aspect, the invention relates to pharmaceutical compositions comprising:
(a) a cell-cycle control agent selected from:
(i) compounds of the Formula I: 
xe2x80x83wherein:
R1 is selected from: 
R2 is a substituted or unsubstituted: carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure; where each optional substituent for R2 is independently a halogen (e.g., chloro, iodo, bromo, or fluoro); oxygen (xe2x95x90O); haloalkyl (e.g., trifluoromethyl); C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; hydroxyl; C1-6-alkoxyl; carbocyclic cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl); carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic aryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester;
(ii) pharmaceutically acceptable salts of compounds of the Formula I; and
(iii) prodrugs and pharmaceutically active metabolites of compounds of the Formula I or pharmaceutically acceptable salts thereof; and
(b) a pharmaceutically acceptable carrier.
Such compositions are useful as inhibitors of mammalian CDK/cyclin complexes, insect CDK, or fungal CDK complexes. Such compositions are also useful for controlling proliferation, differentiation, and/or apoptosis. Thus, in one general aspect the invention is directed to pharmaceutical compositions containing pharmaceutically effective amounts of cell-cycle control agents.
In a preferred embodiment, the invention is directed to potent cell-cycle control agents where R2 in Formula I is an ortho-substituted aryl ring structure (e.g., o-substituted phenyl). Particularly preferred among such agents are those in which R2 is an o-disubstituted phenyl.
The invention further relates to methods of using cell-cycle control agents for treating diseases or disorders mediated by CDK inhibition, especially those mediated by CDK4 and/or CDK2 inhibition. More particularly, the invention is directed to methods of treating malignancies or cancer-type disorders by administering a pharmaceutical composition comprising a cell-cycle control agent. Additionally, the invention relates to the use of cell-cycle control agents to prevent or treat mycotic infections.
Other aspects, advantages, and preferred features of the invention will become apparent from the detailed description below.
In one general embodiment, the invention relates to pharmaceutical compositions each comprising:
(a) an amount of a cell-cycle control agent effective to inhibit a CDK, the cell-cycle control agent being:
(i) a compound of the Formula I: 
xe2x80x83wherein:
R1 is a substituted or unsubstituted group selected from: C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; C1-6-alkoxyl; carbocylic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl; carbonyl; ether; (C1-6-alkyl)-carbonyl; (C1-6-alkyl)-aryl; (C1-6-alkyl)-cycloalkyl; (C1-6-alkyl)-(C1-6-alkoxyl); aryl-(C1-6-alkoxyl); thioether; thiol; and sulfonyl; and
R2 is a substituted or unsubstituted, carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, ring structure;
where each optional substituent for R1 and R2 is independently a halogen; haloalkyl; C1-6-alkyl; C1-6-alkenyl; C1-6-alkynyl; hydroxyl; C1-6 alkoxyl; amino; nitro; thiol; thioether; imine; cyano; amido; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; or ester;
(ii) a pharmaceutically acceptable salt of a compound of the Formula I; or
(iii) a prodrug or pharmaceutically active metabolite of a compound of the Formula I or a pharmaceutically acceptable salt thereof; and
(b) a pharmaceutically acceptable carrier.
In another general embodiment, each optional substituent for R1 and R2 may be independently selected from, in addition to the above-identified groups, the following groups: oxygen; carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, cycloalkyl; and carbocyclic or heterocyclic, monocyclic or fused or non-fused polycyclic, aryl. Such substituents may optionally be further substituted with a substituent selected from such groups.
Examples for the moiety R1 include substituted or unsubstituted aryl and alkyl, such as phenyl, pyridyl, benzimidazole, benzyl, and C1-6-alkyl. In a preferred embodiment, these groups have one or more substituents selected from: halogen; oxygen; haloalkyl; C1-6-alkyl; cycloalkyl; heterocycloalkyl; aryl; hydroxyl; C1-6 alkoxyl; amino; nitro thioether; cyano; amido; carboxyl; sulfonamido; ketone; aldehyde; and ester.
Other preferred moieties for R1 are phenyl groups substituted by an alkylamine or pyridine group having optional substituents selected from the group described in the above paragraph for R1. The alkylamine substitutent may be a 5- to 7-membered heterocycloalkyl optionally containing, in addition to the nitrogen ring atom, one or more heteroatoms selected from N, O and S.
Examples of such preferred R1 groups include phenyl substituted in the para position with a heterocycloalkyl, for example piperidinyl, piperazinyl, thiazinyl, or morpholinyl, or a pyridyl group. The following are examples of preferred R1 groups: 
Other particularly preferred R1 groups include phenyl groups substituted with carbonyl or sulfonamide moieties, wherein the carbonyl carbon and sulfonamide nitrogen are optionally further substituted. The following are examples of preferred R1 groups: 
where R3 is selected from C1-C6 alkyl, C1-C6 alkoxy, aryl, aryloxy, and amine.
Other preferred examples for the moiety R1 include substituted or unsubstituted phenyl, alkylbenzyl, alkyl, benzyl carboxyl ester, benzyloxyphenyl, dimethylaminophenyl, pyridinyl, phenethyl, alkylcarboxyl, alkylpiperidinyl, phenylamino, cyclohexyl, benzylcarboxylalkyl, benzylnitro, phenyl-alkoxyl, ethyl benzoate, benzyl carboxyl, alkylbenzoimidazole, benzoimidazole, benzyldimethylamino, pyridinyl-sulfanyl, cyanobenzyl, and phenyl sulfamyl.
In preferred embodiments, R2 in Formula I is a bulky group such as a substituted or unsubstituted carbocyclic or heterocyclic monocycle, or a substituted or unsubstituted fused or non-fused carbocyclic or heterocyclic polycycle. More preferably, R2 is a substituted (carbo or poly)-(monocycle or polycycle); even more preferably, R2 is such a cyclic ring structure bearing a substituent at the position adjacent or vicinal to the point of attachment (to the core structure).
For example, preferred species for R2 include an ortho-substituted aromatic ring structure such as o-substituted phenyl or thienyl, or a 1,2-substituted cycloalkyl or cycloalkenyl ring structure such as 2-substituted cyclopent-1-enyl. Particularly preferred examples for the moiety R2 include substituted or unsubstituted: o-halophenyl (e.g., o-fluorophenyl, o-chlorophenyl, o-iodophenyl, or o-bromophenyl), o-nitrophenyl, o-aminophenyl, o-C1-6-alkylphenyl, o-C1-6-alkoxyphenyl (e.g., o-methoxyphenyl or o-ethoxyphenyl), o-C1-6-alkoxybenzothiophenyl, o-methylthiophenyl, benzonitrile, and carboxybenzyl. Particularly preferred examples for the moiety R2 also include ortho-disubstituted aryls, for example, 2,6-dihalophenyl (e.g., 2,6-difluorophenyl) and 2-halo-6-trifluoromethylphenyl (e.g., 2-fluoro-6-trifluoromethylphenyl). Compounds of the Formula I where R2 is a 1,2-substituted cyclic ring structure, optionally having one or more additional substituents, such as an ortho-substituted aryl having another substituent at the para position, have been surprisingly found to be potent CDK inhibitors.
Particularly preferred examples of compounds of Formula I include: 
Other particularly preferred examples of compounds of Formula I include: 
Pharmaceutical compositions according to the invention may, alternatively or in addition to a compound of the Formula I, comprise as an active ingredient a pharmaceutically acceptable salt of a compound of the Formula I, or a prodrug or pharmaceutically active metabolite of such a compound or salt. Such compounds, salts, prodrugs, and metabolites are sometimes referred to herein collectively as xe2x80x9ccell-cycle control agents.xe2x80x9d
Compositions in accordance with the invention inhibit the kinase activity of CDK/cyclin complexes, such as those active in the G0 or G1 stage of the cell cycle, e.g., CDK2, CDK4, and/or CDK6 complexes. Preferred compositions of the invention contain cell-cycle control agents having an inhibition constant against CDK4 or a CDK4/D-type cyclin complex of about 1 xcexcM or less, more preferably of about 500 nM or less, even more preferably of about 200 nM or less, and most preferably of about 100 nM or less. Especially preferred compounds of the invention include those having a CDK4/cyclin D3 inhibition constant (Ki CDK4/D3) of about 100 nM or less. Other preferred compositions of the invention contain cell-cycle control agents having an inhibition constant against CDK2 or a CDK2/E-type cyclin complex of about 1 xcexcM or less, more preferably of about 500 nM or less, even more preferably of about 200 nM or less, and most preferably of about 100 nM or less.
Certain compounds of the Formula I may exist in various stereoisomeric or tautomeric forms. The present invention encompasses all such CDK-inhibiting compounds, including active compounds in the form of essentially pure enantiomers, racemic mixtures, and tautomers.
The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means pharmacologically acceptable and substantially non-toxic to the subject being administered the cell-cycle control agent. Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane-disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and fumaric acid. Exemplary base-addition salts include those derived from ammonium hydroxides (e.g., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from organic bases such as carbonates, bicarbonates, amines, benzylamines, piperidines, and pyrrolidines.
The term xe2x80x9cprodrugxe2x80x9d refers to a metabolic precursor of a compound of the Formula I (or a salt thereof) that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the Formula I. The term xe2x80x9cactive metabolitexe2x80x9d refers to a metabolic product of a compound of the Formula I that is pharmaceutically acceptable and effective. Prodrugs and active metabolites of compounds of the Formula I may be determined using techniques known in the art.
Cell-cycle control agents in accordance with the invention are useful as pharmaceuticals for treating proliferative disorders in mammals, especially humans, marked by unwanted proliferation of endogenous tissue. Compounds of the Formula I may be used for treating subjects having a disorder associated with excessive cell proliferation, e.g., cancers, psoriasis, immunological disorders involving undesired proliferation of leukocytes, and restenosis and other smooth-muscle disorders. Furthermore, such compounds may be used to prevent de-differentiation of post-mitotic tissue and/or cells.
Pharmaceutical compositions or preparations of the invention comprise a pharmaceutically acceptable carrier and an effective amount of at least one cell-cycle control agent. The term xe2x80x9ceffective amountxe2x80x9d means an amount that significantly inhibits proliferation and/or prevents de-differentiation of a eukaryotic cell, e.g., a mammalian, insect, plant, or fungal cell, and is effective for the indicated utility, e.g., specific therapeutic treatment.
The specific dosage amount of a cell-cycle control agent being administered to obtain therapeutic or inhibitory effects, of course, may be determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. An exemplary total daily dose of a cell-cycle control agent, which may be administered in single or multiple doses, contains a dosage level of from about 0.01 mg/kg body weight to about 50 mg/kg body weight.
The cell-cycle control agents of the invention may be administered by any of a variety of suitable routes, such as orally, rectally, transdermally, subcutaneously, intravenously, intramuscularly, or intranasally. The cell-cycle control agents are preferably formulated into compositions suitable for the desired routes before being administered.
A pharmaceutical composition or preparation according to the invention comprises an effective amount of a cell-cycle control agent and a pharmaceutically acceptable carrier, such as a diluent or excipient for the agent. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material acting as a vehicle, excipient, or medium for the active ingredient(s). Compositions according to the invention may be made by admixing the active ingredient(s) with a carrier, or diluting it with a carrier, or enclosing or encapsulating it within a carrier, which may be in the form of a capsule, sachet, paper container, or the like. Exemplary ingredients, in addition to one or more cell-cycle control agents and any other active ingredients, include Avicel (microcrystalline cellulose), starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, peanut oil, olive oil, glyceryl monostearate, Tween 80 (polysorbate 80), 1,3-butanediol, cocoa butter, beeswax, polyethylene glycol, propylene glycol, sorbitan monostearate, polysorbate 60, 2-octyldodecanol, benzyl alcohol, glycine, sorbic acid, potassium sorbate, disodium hydrogen phosphate, sodium chloride, and water.
The compositions may be prepared in any of a variety of forms suitable for the desired mode of administration. For example, pharmaceutical compositions may be prepared in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments (e.g., containing up to 10% by weight of a cell-cycle control agent), soft-gel and hard-gel capsules, suppositories, sterile injectable solutions, sterile packaged powders, and the like.
A pharmaceutical composition according to the invention comprises a cell-cycle control agent and, optionally, one or more other active ingredients, such as a known antiproliferative agent that is compatible with the cell-cycle control agent and suitable for the indication being treated. In a preferred embodiment, a pharmaceutical composition of the invention includes an effective amount of a cell-cycle control agent of the Formula I as an active ingredient.